Drug stability and release kinetics of a somatostatin analogue formulated in polymeric biodegradable microspheres

PLGA (poly (lactide-co-glycolide)) microspheres have been shown to safely and effectively deliver antibiotics and bioactive peptides for therapeutic treatment in humans and animals. The biodegradable polymer allows for drug delivery from several weeks to several months. The question of chemical stability of drug molecules during the time course of drug delivery is a major focus of this dissertation. Literature reports have indicated that certain bioactive peptides chemically react with polyester functional groups within the PLGA dosage form to create glycoyl and lactoyl substituted compounds, which as a result are adduct species. It was subsequently hypothesized that based on the structure of octreotide acetate, a therapeutic peptide used for the treatment of acromegaly, the same adduct species would form. In this dissertation, octreotide adduct species identified from mass spectra (peptide m/z value + 58 m/z for glycoyl adduct or + 72 m/z for lactoyl adduct) were postulated to form by an acylation reaction mechanism. The discovery occurred during in vitro and in vivo experiments where octreotide microspheres were incubated in aqueous media of adjusted pH and in the subcutaneous region of live Sprague-Dawley male rats, respectively. During both sets of incubation studies, microspheres composed of greater lactide content in the polymer co-monomer ratio (i.e. PLA (poly(l-lactide)) versus PLGA 85:15 and PLGA 50:50) displayed enhanced peptide stability thereby minimizing the adduct formation.; A secondary focus of this dissertation was to implement formulation and processing strategies to minimize chemical reactivity and optimize drug release kinetics. PLA polymers, consequently, were extensively utilized for the further formulation development due to enhanced stabilizing properties. The polymer, however, did not allow for sustained release of drug over time with a rapid burst effect leaving minimal in vivo serum concentrations after 7 days post-administration to rats. Hence, processing alterations were implemented where the oil/water dispersion technique was changed to an oil/oil dispersion technique during manufacturing, thus allowing for suitable release kinetics in vivo. These microspheres were subjected to further in vitro incubation experiments where the onset of adduct formation was found to correlate with onset of polymer mass in neutral buffer media.